Improving long-term survival in diffuse intrinsic pontine glioma

ABSTRACT

Introduction

Diffuse intrinsic pontine glioma (DIPG) is an almost universally fatal pediatric brain cancer. There has been no improvement in event-free survival (EFS) or overall survival (OS) despite immense effort through a multitude of clinical trials to find a cure. Recently, there has been a surge in the knowledge of DIPG biology, including the discovery of a recurrent H3F3A mutation in over 80% of these tumors.

Areas covered

The authors review the most recent approaches to diagnosis and treatment of DIPG including chemotherapy, biologics, surgical approaches, and immunotherapy.

Expert opinion

The authors propose four main opportunities to improve long-term survival. First, patients should be enrolled in scientifically sound clinical trials that include molecularly profiling either via stereotactic biopsy or liquid biopsy. Second, clinical trials should include more innovative endpoints other than traditional EFS and OS such as MRI/PET imaging findings combined with surrogates of activity (e.g. serial liquid biopsies) to better ascertain biologically active treatments. Third, innovative clinical trial approaches are needed to help allow for the rapid development of combination therapies to be tested. Finally, effort should be concentrated on reversing the effects of the histone mutation, as this malfunctioning development program seems to be key to DIPG relentlessness.

KEYWORDS:

• Chemotherapy
• DIPG
• H3K27M
• HDACS
• immunotherapy
• oncohistones
• radiation therapy

Article highlights

• DIPG is a common pediatric high-grade brain tumor with less than 5% overall survival.

• Previously a radiographic diagnosis, surgical biopsy has been proven safe in most patients.

• Recurrent mutations in histone (H3K27M) have been found in the majority of DIPG causing epigenetic dysregulation and aberrant transcription.

• Targeting the resultant epigenetic changes may be important in stopping DIPG growth.

• Newer techniques to bypass the blood–brain barrier via convection-enhanced delivery of therapies directly to the tumor show promise.

• DIPG is an immunologically ‘cold’ tumor, but multiple immunotherapies are trying to induce the immune destruction of DIPG.

• Ultimately, DIPG treatment will have to be multi-model if we have any hope of improving survival.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

A reviewer on this manuscript serves on the Board of Directors of Oncoceutics which manufactures the experimental agent ONC 201 which has been briefly mentioned in this review paper. Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.

Additional information

Funding

This paper was not funded.